Variable Gene Defects and Pneumococcal Susceptibility

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DESCRIPTION (provided by applicant): This is a competitive renewal application to continue studies of antibody (Ab) immunity to Streptococcus pneumoniae (pneumococcus). The focus of the proposal is on the relationship between the immune status of the host and Ab protection against pneumococcal pneumonia. Pneumococcal pneumonia is the leading cause of community acquired pneumonia in the U.S. and globally. Since 2000, use of the pneumococcal conjugate vaccine has led to a dramatic decline in invasive pneumococcal disease in children and in adults due to herd immunity. Nonetheless, there has been an increase in non-vaccine serotypes (ST), including ST3, which is the focus of this application. The elderly and patients with immunocompromised states and co-morbid conditions continue to be at the highest risk for pneumococcal disease. The emergence of non-vaccine STs, uncertainty as to whether pneumococcal capsular polysaccharide (PPS) vaccines prevent pneumonia in adults, and the increased number of immunocompromised and elderly people in the U.S., underscore the need for a better understanding of mechanisms of PPS vaccine efficacy and failure, particularly in immunocompromised patients. Several novel findings from our group during the previous finding period are relevant to this question: 1) monoclonal antibodies (MAbs) that were not opsonophagocytic in vitro were able to protect mice against pulmonary challenge with pneumococcus; 2) the efficacy of non-opsonophagocytic MAbs in mice was associated with modulation of the inflammatory response; and 3) CD8 T cells were required for a PPS-protein conjugate and immune serum to protect mice against lethal pulmonary challenge with ST3 pneumococcus. The hypothesis of this proposal is that vaccine efficacy against pneumococcal pneumonia requires Abs that control of the bacterial burden and modulate the immune response and that this depends on collaboration between Ab and components of cellular immunity. The specific aims are: 1) To determine the role that CD8 T cells play in protection against ST3 pneumonia in mice; 2) To determine the contribution of T cells and Ab type to Ab protection against ST3 in mice; 3) To determine the role of PMNs and macrophages in Ab protection against ST3 pneumonia in mice. The studies we propose will advance understanding of vaccine efficacy and reveal novel mechanisms of Ab immunity against pneumonia and have direct relevance to prevention and treatment of pneumococcal pneumonia, particularly in immunocompromised patients. PUBLIC HEALTH RELEVANCE: Use of a pediatric conjugate vaccine (pneumococcal vaccine) for Streptococcus pneumoniae has resulted in a reduction in the incidence of invasive pneumococcal disease in adults and children. This is a major advance. However, the emergence of pneumococcal strains that are not in the vaccine, particularly in immunocompromised patients, and uncertainty as to whether the current pneumococcal vaccine for adults prevents pneumonia, underscore the need for improved vaccines, particularly for immunocompromised patients. Pneumococcal vaccines work by eliciting antibodies (Ab) that prevent disease. The aims of this application, which propose to reveal the importance of the immune status of the host to Ab protection against pneumonia, have direct relevance to prevention and treatment of pneumococcal pneumonia, particularly in immunocompromised patients. The proposed studies will advance our understanding of how pneumococcal vaccine works.